Investigating the incidence, impact, and severity of pulmonary complications after hepatectomy: A single institution experience.

BACKGROUND: Postoperative pulmonary complications are a common cause of postoperative morbidity in patients undergoing hepatectomy. This study aimed to identify risk factors, define severity, and evaluate the impact of postoperative pulmonary complications on postoperative morbidity after hepatectomy. METHOD: We used a prospective database in identifying all hepatectomies from 2013 to 2018. The database was then augmented using extensive review of medical records. The Strasburg system was used in categorizing resections per complexity: major hepatic resection and minor hepatic resection, whereas the Clavien-Dindo system was used in defining postoperative pulmonary complications per severity. Potential confounders were controlled for on multiple regression models. RESULTS: A total of 702 cases were identified: major hepatic resection 413 (60%) and minor hepatic resection 289 (40%). Patients demonstrated comparable characteristics, but the postoperative pulmonary complications group was more likely to have chronic obstructive pulmonary disease (10% vs 5%; P = .02). Severe postoperative pulmonary complications among major hepatectomy was observed in 38 patients (13%). Predictors for severe postoperative pulmonary complications requiring intervention included postoperative liver failure (odds ratio = 2.8; P = .002) and biliary fistula (odds ratio = 3.5; P = .001). In addition, the occurrence of severe postoperative pulmonary complications markedly hindered recovery, increasing length of stay by 4.4-fold and readmission rates by 3-fold (P < .001). On multivariable analysis, postoperative pulmonary complications significantly increase postoperative length of stay (8 vs 5 days; P < .001) and readmission (odds ratio = 3.2; P = .001). Mortality was similar (1% vs 4%; P = .066). CONCLUSION: Postoperative pulmonary complications are a major cause of delayed recovery and worse outcomes after hepatectomy. Further, postoperative liver failure and biliary fistula can predict the occurrence of severe postoperative pulmonary complications among major hepatic resection and the associated need for readmission with these complications.

Outcomes in Endoscopic and Operative Transgastric Pancreatic Debridement.

OBJECTIVES: Select patients with anatomically favorable walled off pancreatic necrosis may be treated by endoscopic (Endo-TGD) or operative (OR-TGD) transgastric debridement (TGD). We compared our experience with these 2 approaches. SUMMARY BACKGROUND DATA: Select necrotizing pancreatitis (NP) patients are suitable for TGD which may be accomplished endoscopically or surgically. Limited experience exists contrasting these techniques exists. METHODS: Patients undergoing Endo-TGD and OR-TGD at a single, high-volume pancreatic center between 2008 and 2019 were identified from a prospective database. Patient characteristics, procedural details, and outcomes of these 2 groups were compared. RESULTS: Among 498 NP patients undergoing necrosis intervention, 160 (32%) had TGD: 59 Endo-TGD and 101 OR-TGD. The groups were statistically similar in age, comorbidity, pancreatitis etiology, necrosis anatomy, pancreatitis severity, and timing of TGD from pancreatitis insult. OR-TGD required 1.1 ±â€Š0.5 and Endo-TGD 3.0 ±â€Š2.0 debridements/patient. Fewer hospital readmissions and repeat necrosis interventions, and shorter total inpatient length of stay were observed in OR-TGD patients. New-onset organ failure [Endo-TGD (13%); OR-TGD (13%); P = 1.0] was similar between groups. Hospital length of stay after TGD was significantly longer in patients undergoing Endo-TGD (13.8 ±â€Š20.8 days) compared to OR-TGD (9.4 ±â€Š6.1 days; P = 0.047). Mortality was 7% in Endo-TGD and 1% in OR-TGD (P = 0.04). CONCLUSIONS: Operative and endoscopic transgastric debridement achieve necrosis resolution with different temporal and procedural profiles. Clear multidisciplinary communication is essential to determine appropriate approach to individual necrotizing pancreatitis patients.

Novel Preoperative Patient-centered Surgical Wellness Program Impacts Length of Stay Following Pancreatectomy.

BACKGROUND/AIM: We created a novel, preoperative wellness program (WP) that promotes recovery. This study assessed its impact on patient outcomes after pancreatectomy. PATIENTS AND METHODS: Pancreatoduodenectomies (PD) and distal pancreatectomies (DP) performed from 2015 to 2018 were reviewed using our institutional NSQIP database. Patients in the WP had their medical conditions optimized and were provided with the following: chlorhexidine, topical mupirocin, incentive spirometer, and immune-nutrition supplements. RESULTS: Out of a total of 669 pancreatectomy patients (411 PD, 258 DP), 308 were enrolled in the WP (188 PD, 120 DP). In the PD subgroup, on multivariable analysis (MVA), the WP patients had shorter lengths of hospital stay (LOS) (12 vs. 10 days, p<0.001). On MVA, WP patients had less post-op transfusion (20 vs. 10%, p=0.027). For the combined groups on MVA, LOS continued to be significant (OR=0.89, 95%CI=0.82-0.97, p<0.007). CONCLUSION: A preoperative patient centered WP may reduce the length of stay.

Preoperative Nomogram Predicts Non-home Discharge in Patients Undergoing Pancreatoduodenectomy.

BACKGROUND: In patients undergoing pancreatoduodenectomy, non-home discharge is common and often results in an unnecessary delay in hospital discharge. This study aimed to develop and validate a preoperative prediction model to identify patients with a high likelihood of non-home discharge following pancreatoduodenectomy. METHODS: Patients undergoing pancreatoduodenectomy from 2013 to 2018 were identified using an institutional database. Patients were categorized according to discharge location (home vs. non-home). Preoperative risk factors, including social determinants of health associated with non-home discharge, were identified using Pearson's chi-squared test and then included in a multiple logistic regression model. A training cohort composed of 80% of the sampled patients was used to create the prediction model, and validation carried out using the remaining 20%. Statistical significance was defined as P < 0.05. RESULTS: Seven hundred sixty-six pancreatoduodenectomy patients met the study criteria for inclusion in the analysis (non-home, 126; home, 640). Independent predictors of non-home discharge on multivariable analysis were age, marital status, mental health diagnosis, functional health status, dyspnea, and chronic obstructive pulmonary disease. The prediction model was then used to generate a nomogram to predict likelihood of non-home discharge. The training and validation cohorts demonstrated comparable performances with an identical area under the curve (0.81) and an accuracy of 84%. CONCLUSION: A prediction model to reliably assess the likelihood of non-home discharge after pancreatoduodenectomy was developed and validated in the present study.

Insurance Type and Marital Status Impact Hospital Length of Stay After Pancreatoduodenectomy.

BACKGROUND: Recognition of the impact of social determinants on health care and surgical outcomes is imperative to improve patient care. This study aims to examine the impact social determinants have on hospital length of stay (LOS) after pancreatoduodenectomy (PD). METHODS: Retrospective review of a prospective American College of Surgeons-National Surgical Quality Improvement Program database identified patients who underwent PD from 2013 to 2018. Patients were categorized by insurance type (public/private/multiple), and electronic medical record review was performed to obtain distance from home, marital status, and race. Public insurance included Medicare and Medicaid; multiple types were defined as public insurance supplemented by a private insurance. Univariable analysis was used to identify potential confounders. Significant differences (P < 0.05) were controlled for using multivariable regression models to examine the effect of variables on LOS. RESULTS: About 813 PDs were included (n = 341 public; n = 238 private; and n = 234 multiple). Patients with public insurance had significantly longer LOS than patients with private on univariate (P < 0.001) and multivariable analyses (P = 0.021) (8 versus 7 d). Patients with multiple insurance types showed significantly increased LOS compared with patients with private on univariable (P < 0.001) and multivariable analyses (P = 0.006) (8 versus 7 d). Single patients had significantly longer LOS compared with married patients on univariable (P = 0.012) and multivariable analyses (P = 0.005) (8 versus 7 d). Distance from home, race, gender, or age did not have a significant impact on LOS. CONCLUSIONS: Single patients and patients with public or multiple insurance types are more likely to have longer hospital LOS after PD. These findings will enable physicians to identify patients at risk and target them for enhanced recovery programming.

Use of primary surgical drains in synchronous resection for colorectal liver metastases: a NSQIP analysis of current practice paradigm.

BACKGROUND: There are no studies examining the use of subhepatic drains after simultaneous resection of synchronous colorectal liver metastases (sCRLM). This study aimed to (1) describe the current practices regarding primary drain placement, (2) evaluate drain efficacy in mitigating postoperative complications, and (3) determine impact of drain maintenance duration on patient outcomes. METHODS: The ACS-NSQIP targeted data from 2014 to 2017 were analyzed. Propensity score of surgical drain versus no drain cohorts was performed. Main study outcomes were mortality, major morbidity, organ/space surgical site infection (SSI), secondary drain/aspiration procedure, and any septic events. Additional univariate/multivariate logistic analyses were performed to identify associations with drain placement and duration. Major hepatectomy was defined as formal right hepatectomy and any trisectionectomy. RESULTS: 584 combined liver and colorectal resection (CRR) cases were identified. Open partial hepatectomy with colectomy was the most common procedure (70%, n = 407). Nearly 40% of patients received surgical drains (n = 226). Major hepatectomy, lower serum albumin, and no intraoperative portal vein occlusion (Pringle maneuver) were significantly associated with drain placement (p < 0.05). In the matched cohort (n = 190 in each arm), patients with surgical drains experienced higher rates of major morbidity (30% vs 12%), organ/space SSI (16% vs 6%), postoperative drain/aspiration procedures (9% vs 3%), and sepsis/septic shock (12% vs 4%) (all p < 0.05). Patients with severely prolonged drain removal, defined as after postoperative day 13 (POD13), had higher risk of postoperative morbidity compared to those with earlier drain removal (p < 0.01). 30-day mortality rate was not significantly different between the two groups. CONCLUSION: Primary surgical drains were placed in a substantial percentage of patients undergoing combined resection for sCRLM. This case-matched analysis suggested that surgical drains are associated with an increase in postoperative morbidity. Postoperative drain maintenance past 13 days is associated with worse outcomes compared to earlier removal.

Transient Biliary Fistula After Pancreatoduodenectomy Increases Risk of Biliary Anastomotic Stricture.

BACKGROUND: Biliary fistula after pancreatoduodenectomy (PD) is associated with significant morbidity and mortality. The aim of this study was to determine the risk of early postoperative biliary fistula for developing biliary anastomotic stricture after PD. METHODS: Retrospective review of all PD performed for various indications at a single institution between 2013 and 2018. Postoperative biliary fistulae were graded according to the International Study Group of Liver Surgery (ISGLS) as grade A-C. Multivariable analysis was performed for all comparative patient subgroups. RESULTS: A total of 843 patients underwent PD for malignant (68%) and benign (32%) indications. Postoperative biliary fistula developed in 66 (8%) patients; ISGLS grade A in 29 (3%), grade B in 32 (4%), and grade C in 5 (0.6%). Ninety-day mortality was 3% (25 patients). The remaining 818 patients were evaluated with a median follow-up of 16 months (IQR, 5-32 months). Biliary anastomotic stricture developed in 41 (5%) patients at a median of 10 months (IQR, 6-18 months) postoperatively. Strictures were managed with percutaneous (27 patients, 66%) or endoscopic (14 patients, 34%) stenting. No biliary stricture required operative anastomotic revision. Postoperative biliary fistula (HR, 4.4; 95% CI, 2.0-9.9; P = 0.0002) was associated with biliary anastomotic stricture; an increased risk for biliary anastomotic stricture was seen in patients with grade A (HR, 6.4; 95% CI, 2.4-16.9; P = 0.0002) and grade B (HR, 3.6; 95% CI, 1.2-10.9; P = 0.02) postoperative biliary fistula. CONCLUSION: Postoperative biliary fistula after pancreatoduodenectomy, including clinically insignificant, transient biliary fistula, is associated with an increased risk of a late biliary anastomotic stricture requiring stenting.

A Quantitative Global Proteomics Approach Identifies Candidate Urinary Biomarkers That Correlate With Intraductal Papillary Mucinous Neoplasm Dysplasia.

OBJECTIVES: A proteomic discovery study was performed to determine if urine possesses a unique biosignature that could form the basis for a noninvasive test able to predict intraductal papillary mucinous neoplasm (IPMN) dysplasia. METHODS: Urine was collected from patients undergoing surgery for IPMN (72 low/moderate, 27 high-grade/invasive). Quantitative mass spectrometry-based proteomics was performed. Proteins of interest were identified by differential expression analysis followed by principal component analysis. RESULTS: Proteomics identified greater than 4800 urinary proteins. Low/moderate and high-grade/invasive IPMN were distinguished by 188 proteins (P < 0.05). Following principal component analysis and heatmap visualization, vitamin D binding protein (DBP), apolipoprotein A1 (APOA1), and alpha-1 antitrypsin (A1AT) were selected. The proteomic abundance of DBP (median [interquartile range]) was significantly higher for high-grade/invasive than for low/moderate IPMN (219,735 [128,882-269,943] vs. 112,295 [77,905-180,773] normalized reporter ion intensity units; P = 0.001). Similarly, APOA1 was more abundant in the high-grade/invasive than low/moderate groups (235,420 [144,933-371,247] vs 150,095 [103,419-236,591]; P = 0.0007) as was A1AT (567,514 [358,544-774,801] vs 358,393 [260,850-477,882]; P = 0.0006). CONCLUSIONS: Urinary DBP, APOA1, and A1AT represent potential biomarker candidates that may provide a noninvasive means of predicting IPMN dysplastic grade.

Secretin-induced Duodenal Aspirate of Pancreatic Juice (SIDA): Utility of Commercial Genetic Analysis.

BACKGROUND: Secretin-induced duodenal aspiration (SIDA) of pancreatic duct fluid has been proposed for pancreatic neoplasm screening in very high-risk patients. We sought to determine the clinical yield and safety of commercially-analyzed SIDA samples in patients at moderately elevated risk. PATIENTS AND METHODS: A prospectively maintained institutional database of pancreatic fluid DNA profiles was retrospectively reviewed. RESULTS: Fifty-seven patients underwent SIDA testing, most commonly for intraductal papillary mucinous neoplasms (n=43) and not otherwise specified solitary cysts (n=9). SIDA mutation yield was low compared to 37 concomitant endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) samples of pancreatic fluid: KRAS (2.5% vs. 40.0%), GNAS (2.6% vs. 11.1%) and allelic loss of heterozygosity (3.1% vs. 0%). Patients undergoing SIDA alone experienced no complications while 3 patients with concomitant EUS-FNA had post-procedural pancreatitis. CONCLUSION: The genetic yield of commercially-analyzed SIDA samples was relatively low in a moderately elevated risk cohort. SIDA testing may have a better safety profile than EUS-FNA.

Operative pancreatic debridement: Contemporary outcomes in changing times.

BACKGROUND/OBJECTIVES: Operative pancreatic debridement (OPD) is the historic gold standard for treating necrotizing pancreatitis (NP). Recent success with minimally invasive NP treatment approaches have raised the question of which NP patients require OPD. We therefore sought to define contemporary outcomes of NP patients undergoing OPD. METHODS: A retrospective analysis was performed of 116 consecutive NP patients undergoing OPD using a prospectively maintained institutional NP database between 2006 and 2018. RESULTS: 86 (74%) patients underwent open pancreatic debridement (OD) and 30 (26%) underwent open transgastric debridement (TGD). Median follow-up was 16 months (interquartile range [IQR], 8-45 months). Median age was 51 years (IQR, 43-65 years); 73 (63%) were male. Pancreatitis etiology included biliary (53%), alcohol (22%), and idiopathic/other (25%). Median time from diagnosis to OPD was 64.5 days (IQR, 32-114.5 days). Mean APACHE-II score was: admission 8.5 (standard deviation [SD], 5.9); worst 12.6 (SD, 7.9); preoperatively 7.2 (SD, 4.6). 40 patients (34%) were initially managed with minimally invasive techniques (percutaneous drain only in 24, endoscopic only in 6, combination in 10). Median postoperative length of stay was 11 days (IQR, 7-19 days). 90-day morbidity and mortality were 70% and 2%, respectively. CONCLUSIONS: NP patients who require OPD are critically and chronically ill. OPD is associated with substantial morbidity, but acceptable mortality in an experienced center with multidisciplinary support. This large contemporary series demonstrates that in properly selected patients, OPD remains an important treatment for NP.

Utility of DNA Profiling From Main Pancreatic Duct Fluid by Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography to Screen for Malignant Potential.

OBJECTIVES: The yield of genetic testing of main pancreatic duct (MPD) fluid collected during endoscopic retrograde cholangiopancreatography (ERCP) versus endoscopic ultrasound-guided fine-needle aspiration is unclear. METHODS: Consecutive MPD fluid samples obtained by endoscopic ultrasound/ERCP with DNA profiling were reviewed, excluding specimens designated "no amplification." Invasive disease included invasive cancer or malignant cytology. RESULTS: One hundred ten samples from 109 patients who underwent ERCP (n = 32) or endoscopic ultrasound-guided fine-needle aspiration (n = 78) were analyzed (2007-2018). Leading indications were dilated MPD and suspected intraductal papillary mucinous neoplasm. Elevated DNA quantity, KRAS, loss of heterozygosity (LOH), and GNAS mutations occurred in 61.5%, 25.5%, 16.4%, and 8.7% of samples, respectively. Elevated DNA quantity occurred more frequently in ERCP samples (84.4% vs 51.9%, P = 0.002); other mutation yields were similar (P > 0.05). Invasive pathology (P = 0.032) was associated with LOH in the subset of patients who underwent surgery (n = 44). Adverse events occurred more frequently after ERCP (28.1% vs 9.0%, P = 0.016). CONCLUSIONS: Endoscopic MPD fluid sampling may yield genetic data to improve diagnosis and risk stratification. In our surgical cohort, LOH was the sole predictor of invasive pathology. Endoscopic ultrasound-guided fine-needle aspiration of MPD fluid, when possible, is preferred because of superior safety profile.

Cerebellar Purkinje cell activity modulates aggressive behavior.

Although the cerebellum is traditionally associated with balance and motor function, it also plays wider roles in affective and cognitive behaviors. Evidence suggests that the cerebellar vermis may regulate aggressive behavior, though the cerebellar circuits and patterns of activity that influence aggression remain unclear. We used optogenetic methods to bidirectionally modulate the activity of spatially-delineated cerebellar Purkinje cells to evaluate the impact on aggression in mice. Increasing Purkinje cell activity in the vermis significantly reduced the frequency of attacks in a resident-intruder assay. Reduced aggression was not a consequence of impaired motor function, because optogenetic stimulation did not alter motor performance. In complementary experiments, optogenetic inhibition of Purkinje cells in the vermis increased the frequency of attacks. These results suggest Purkinje cell activity in the cerebellar vermis regulates aggression, and further support the importance of the cerebellum in driving affective behaviors that could contribute to neurological disorders.

Performance of candidate urinary biomarkers for pancreatic cancer - Correlation with pancreatic cyst malignant progression?

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMN) are precursors of pancreatic cancer. Potential biomarkers of IPMN progression have not been identified in urine. A few urinary biomarkers were reported to be predictive of pancreatic ductal adenocarcinoma (PDAC). Here, we seek to assess their ability to detect high-risk IPMN. METHODS: Urine was collected from patients undergoing pancreatic resection and healthy controls. TIMP-1(Tissue Inhibitor of Metalloproteinase-1), LYVE-1(Lymphatic Vessel Endothelial Receptor 1), and PGEM(Prostaglandin E Metabolite) levels were determined by ELISA and analyzed by Kruskal-Wallis. RESULTS: Median urinary TIMP-1 levels were significantly lower in healthy controls (n = 9; 0.32 ng/mg creatinine) compared to PDAC (n = 13; 1.95) but not significantly different between low/moderate-grade (n = 20; 0.71) and high-grade/invasive IPMN (n = 20; 1.12). No significant difference in urinary LYVE-1 was detected between IPMN low/moderate (n = 16; 0.37 ng/mg creatinine) and high/invasive grades (n = 21; 0.09). Urinary PGEM levels were not significantly different between groups. CONCLUSIONS: Urinary TIMP-1, LYVE-1, and PGEM do not correlate with malignant potential of pancreatic cysts.

Two open whipples a day: Excessive or efficient.

BACKGROUND: Demand for pancreatic surgery is rising, occasionally necessitating consecutive PDs to be performed by a single surgeon in the same workday. The safety of this practice is unknown. METHODS: Institutional prospective ACS-NSQIP data were reviewed for PDs (2013-2017). Instances where a single surgeon performed two PDs in the same day were a PD pair (PD1, PD2) and compared with univariable analysis. Paired vs. unpaired-PD matched analyses were performed. RESULTS: 661 PDs (25-PD pairs) were performed. PD1 and PD2 revealed similar infectious (12% vs16%), pulmonary (8% vs8%), cardiovascular (12% vs4%), and aggregate (24% vs24%) morbidity (P>0.05). Pancreatic fistula (B + C 0%), delayed gastric emptying (4% vs12%), hospital stay (9.3 vs8.8 days), and 30-day mortality (4% vs4%) were similar (P > 0.05). Matched outcomes were similar except higher cardiovascular morbidity for paired vs. unpaired PD (7% vs0%; P = 0.015). CONCLUSION: With proper patient selection, and in experienced hands at high-volume centers, two consecutive open PDs may be safely performed.

Pancreatic Fluid Interleukin-1ß Complements Prostaglandin E2 and Serum Carbohydrate Antigen 19-9 in Prediction of Intraductal Papillary Mucinous Neoplasm Dysplasia.

OBJECTIVES: We sought to determine if interleukin (IL)-1ß and prostaglandin E2 (PGE2) (inflammatory mediators in pancreatic fluid) together with serum carbohydrate antigen (CA) 19-9 could better predict intraductal papillary mucinous neoplasm (IPMN) dysplasia than individual biomarkers alone. METHODS: Pancreatic cyst fluid (n = 92) collected via endoscopy or surgery (2003-2016) was analyzed for PGE2 and IL-1ß (enzyme-linked immunosorbent assay). Patients had surgical pathology-proven IPMN. Threshold values (PGE2 [>1100 pg/mL], IL-1ß [>20 pg/mL], and serum CA 19-9 [>36 U/mL]) were determined. RESULTS: Levels of IL-1ß were higher in high-grade dysplasia (HGD)/invasive-IPMN (n = 42) compared with low/moderate IPMN (n = 37) (median [range], 54.6 [0-2671] vs 5.9 [0-797] pg/mL; P < 0.001; area under curve [AUC], 0.766). Similarly, PGE2 was higher in HGD/invasive IPMN (n = 45) compared with low/moderate IPMN (n = 47) (median [range], 1790 [20-15,180] vs. 140 [10-14,630] pg/mL; P < 0.001; AUC, 0.748). Presence of elevated PGE2 and IL-1ß (AUC, 0.789) provided 89% specificity and 82% positive predictive value (PPV) for HGD/invasive IPMN. Elevated levels of all 3 provided 100% specificity and PPV for HGD/invasive IPMN. CONCLUSIONS: Cyst fluid PGE2, IL-1ß, and serum CA 19-9 in combination optimize specificity and PPV for HGD/invasive IPMN and may help build a panel of markers to predict IPMN dysplasia.

Activity-dependent structural plasticity after aversive experiences in amygdala and auditory cortex pyramidal neurons.

The brain is highly plastic and undergoes changes in response to many experiences. Learning especially can induce structural remodeling of dendritic spines, which is thought to relate to memory formation. Classical Pavlovian fear conditioning (FC) traditionally pairs an auditory cue with an aversive footshock, and has been widely used to study neural processes underlying associative learning and memory. Past research has found dendritic spine changes after FC in several structures. But, due to heterogeneity of cells within brain structures and limitations of traditional neuroanatomical techniques, it is unclear if all cells included in analyses were actually active during learning processes, even if known circuits are isolated. In this study, we employed a novel approach to analyze structural plasticity explicitly in neurons activated by exposure to either cued or uncued footshocks. We used male and female Arc-dVenus transgenic mice, which express the Venus fluorophore driven by the activity-related Arc promoter, to identify neurons that were active during either scenario. We then targeted fluorescent microinjections to Arc+ and neighboring Arc- neurons in the basolateral area of the amygdala (BLA) and auditory association cortex (TeA). In both BLA and TeA, Arc+ neurons had reduced thin and mushroom spine densities compared to Arc- neurons. This effect was present in males and females alike and also in both cued and uncued shock groups. Overall, this study adds to our understanding of how neuronal activity affects structural plasticity, and represents a methodological advance in the ways we can directly relate structural changes to experience-related neural activity.

Sexually divergent expression of active and passive conditioned fear responses in rats.

Traditional rodent models of Pavlovian fear conditioning assess the strength of learning by quantifying freezing responses. However, sole reliance on this measure includes the de facto assumption that any locomotor activity reflects an absence of fear. Consequently, alternative expressions of associative learning are rarely considered. Here we identify a novel, active fear response ('darting') that occurs primarily in female rats. In females, darting exhibits the characteristics of a learned fear behavior, appearing during the CS period as conditioning proceeds and disappearing from the CS period during extinction. This finding motivates a reinterpretation of rodent fear conditioning studies, particularly in females, and it suggests that conditioned fear behavior is more diverse than previously appreciated. Moreover, rats that darted during initial fear conditioning exhibited lower freezing during the second day of extinction testing, suggesting that females employ distinct and adaptive fear response strategies that improve long-term outcomes.

A rural pathways program for high school students: reinforcing a sense of place.

BACKGROUND AND OBJECTIVES: The affinity model predicts that students from rural areas who train in smaller towns will be more likely to choose rural practice. Most pipeline programs based on this model begin in college or medical school. Many rural students first encounter academic and career planning challenges prior to college, and a few programs are focused on high school students. METHODS: We report pre- and post-program opinions and American College Testing (ACT) practice scores from 151 participants in a high school rural scholar program over the first 10 years of the program. RESULTS: After participation, the students showed significantly more positive opinions about their county's health care resources and their knowledge of career options, and they knew more names of the providers in their county. Their practice ACT scores increased slightly, and their assessment that they were well prepared to take the ACT improved. Seventy-five percent have pursued a health career, and 10% have entered medical school. CONCLUSIONS: A summer program that allows high school students to shadow health professionals in their hometown and study in a virtual classroom can accomplish modest academic gains while producing more positive opinions about the health care in their county. They also report better understanding of the career options available to them.

Collaboration within the M1 aminopeptidase family promotes reproductive success in Caenorhabditis elegans.

Mutations of the puromycin-sensitive aminopeptidase (Psa) orthologs of flies, mice, and plants result in meiotic errors and reduced embryonic viability. Genetic lesions of the Caenorhabditis elegans ortholog of Psa, pam-1, similarly result in dramatic reductions of worm fecundity. The gonads of animals harboring mutant pam-1 alleles display expanded populations of pachytene germinal nuclei and delayed nucleolar disassembly in the developing oocytes, phenotypes that ultimately hinder embryonic viability and overall brood sizes. PAM-1 is a member of the M1 aminopeptidase family and shares a high amount of homology with its M1 paralogs. Comparative analysis of the M1 aminopeptidase family reveals that only nine (including PAM-1) of the 17 annotated M1 aminopeptidases are predicted to be catalytically active. Interestingly, we demonstrate that three of these active M1 paralogs have roles independent of PAM-1 in promoting gametogenesis and fecundity. Simultaneous inhibition of pam-1 and M1 paralogs produces synergistic decreases in overall brood sizes and embryonic viability, exacerbates the germinal phenotypes of pachytene extension and delayed nucleolar disassembly, and unmasks previously hidden phenotypes. Our data suggests that the interdependent functions of multiple M1 aminopeptidases are necessary for reproductive success in C. elegans and lend further credence to the redundant composition of an evolutionarily conserved enzyme family.